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Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation
Sonia Guedan, … , Regina M. Young, Carl H. June
Sonia Guedan, … , Regina M. Young, Carl H. June
Published January 11, 2018
Citation Information: JCI Insight. 2018;3(1):e96976. https://doi.org/10.1172/jci.insight.96976.
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Research Article Immunology

Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation

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Abstract

Successful tumor eradication by chimeric antigen receptor–expressing (CAR-expressing) T lymphocytes depends on CAR T cell persistence and effector function. We hypothesized that CD4+ and CD8+ T cells may exhibit distinct persistence and effector phenotypes, depending on the identity of specific intracellular signaling domains (ICDs) used to generate the CAR. First, we demonstrate that the ICOS ICD dramatically enhanced the in vivo persistence of CAR-expressing CD4+ T cells that, in turn, increased the persistence of CD8+ T cells expressing either CD28- or 4-1BB–based CARs. These data indicate that persistence of CD8+ T cells was highly dependent on a helper effect provided by the ICD used to redirect CD4+ T cells. Second, we discovered that combining ICOS and 4-1BB ICDs in a third-generation CAR displayed superior antitumor effects and increased persistence in vivo. Interestingly, we found that the membrane-proximal ICD displayed a dominant effect over the distal domain in third-generation CARs. The optimal antitumor and persistence benefits observed in third-generation ICOSBBz CAR T cells required the ICOS ICD to be positioned proximal to the cell membrane and linked to the ICOS transmembrane domain. Thus, CARs with ICOS and 4-1BB ICD demonstrate increased efficacy in solid tumor models over our current 4-1BB–based CAR and are promising therapeutics for clinical testing.

Authors

Sonia Guedan, Avery D. Posey Jr., Carolyn Shaw, Anna Wing, Tong Da, Prachi R. Patel, Shannon E. McGettigan, Victoria Casado-Medrano, Omkar U. Kawalekar, Mireia Uribe-Herranz, Decheng Song, J. Joseph Melenhorst, Simon F. Lacey, John Scholler, Brian Keith, Regina M. Young, Carl H. June

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Figure 4

Levels of surface CAR expression influence antitumor effects.

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Levels of surface CAR expression influence antitumor effects.
(A and B) ...
(A and B) T cells were transduced with indicated MOI with lentiviral vectors encoding CAR proteins. CAR expression (A) and mean cell volume (B) was analyzed on day 13 after T cell transduction by flow cytometry. (C) Surface expression of the CAR proteins on human T cells at the time of functional evaluation. Transduction efficiencies are indicated with MFI of the transduced populations in parentheses. (D) Fold-change CAR expression (MFI) in pGK300-BBz and EF-1α-BBz relative to EF-1α-ICOSBBz was analyzed in 3 donors. **P < 0.01 by 1-way ANOVA with Tukey post hoc test. (E) T cell volume during ex vivo expansion in the absence of cognate antigen. Results are expressed as the mean T cell volume (± SD) with n = 2 donors. (F) Representative histograms showing the expression of activation, differentiation, and exhaustion markers in CAR T cell 14 days after stimulation with anti-CD3/CD28 beads. Representative of 2 donors. (G) NSG mice bearing s.c. Capan-2 pancreatic tumors were treated 20 days after tumor implantation with 2 doses of UTD or CAR T cells with the indicated promoter and signaling domain. Tumor volume was analyzed at indicated time points. Results are expressed as the mean tumor volume (± SEM) with n = 7–10 mice per group. Statistical significance: *P < 0.05 by 2-way ANOVA with Tukey’s multiple comparison test.

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